Hmg-coa reductase inhibiting substituted pryido (2,3-d) pyrimidines

ABSTRACT

New substituted pyrido(2,3-d)pyrimidines of the formula ##STR1## can be prepared by reduction of corresponding pyrido(2,3-d)-pyrimidines which are substituted by a ketone radical, and subsequent hydrolysis, cyclization or hydrogenation. The new compounds can be used to inhibit HMG-CoA reductase.

The invention relates to new substituted pyrido(2,3-d)pyrimidines, andto intermediates for their preparation, their preparation and their usein medicaments.

It is known that lactone derivatives isolated from fungal cultures areinhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoAreductase) [mevinolin, EP-A 22,478; U.S. Pat. No. 4,231,938]. Moreover,certain indole derivatives or pyrazole derivatives are inhibitors ofHMG-CoA reductase [EP-A 1,114,027; U.S. Pat. No. 4,613,610].

New substituted pyrido(2,3-d)pyrimidines of the general formula (I)##STR2## in which A - represents a 5- to 7-membered heterocycle whichmay contain up to 4 heteroatoms from the series comprising sulphur,oxygen or nitrogen and which is optionally monosubstituted totrisubstituted by identical or different substituents from the seriescomprising halogen, hydroxyl, trifluoromethyl, straight-chain orbranched alkyl, alkoxy or alkoxycarbonyl each having up to 8 carbonatoms, aryl having 6 to 10 carbon atoms or by a group of the formula--NR¹ R², in which

R¹ and R² are identical or different and

denotes hydrogen, aryl or arylsulphonyl having 6 to 10 carbon atoms orstraight-chain or branched alkyl or alkylsulphonyl having up to 8 carbonatoms, where the last-mentioned radicals are optionally substituted byaryl having 6 to 10 carbon atoms, or

denote a group of the formula --COR³, in which

R³ - denotes straight-chain or branched alkyl or alkoxy having up to 8carbon atoms or phenyl,

represents aryl having 6 to 10 carbon atoms, which is optionallymonosubstituted to pentasubstituted by identical or differentsubstituents from the series comprising straight-chain or branchedalkyl, alkylthio, alkylsulphonyl, alkoxy or alkoxycarbonyl each havingup to 10 carbon atoms, which may in turn be substituted bytrifluoromethyl, hydroxyl, alkoxy having up to 6 carbon atoms, phenyl orphenoxy,

or is substituted by aryl, aryloxy, arylthio or arylsulphonyl having 6to 10 carbon atoms, or by halogen, nitro, cyano, trifluoromethyl,benzyloxy or a group of the formula --NR¹ R², in which

R¹ and R² have the abovementioned meanings, or represents straight-chainor branched alkyl, each having up to 8 carbon atoms

B - represents cycloalkyl having 3 to 8 carbon atoms,

represents trifluoromethyl or straight-chain or branched alkyl having upto 12 carbon atoms, which is optionally substituted by halogen,hydroxyl, cyano, azido, trifluoromethyl, alkylthio, alkylsulphonyl oralkoxy each having up to 8 carbon atoms or by aryl, aryloxy or arylthiohaving 6 to 10 carbon atoms, where the aryl radicals may optionally bemonosubstituted to trisubstituted by identical or different substituentsfrom the series comprising halogen, cyano, trifluoromethyl,trifluoromethoxy, straight-chain or branched alkyl, alkoxy, alkylthio oralkylsulphonyl each having up to 8 carbon atoms, or is substituted by agroup of the formula --NR¹ R² or --COR³, in which

R¹, R² and R³ have the abovementioned meanings,

represents aryl having 6 to 10 carbon atoms, which is optionallysubstituted by halogen, cyano, nitro, trifluoromethyl, straight-chain orbranched alkyl, alkoxy or alkoxycarbonyl each having up to 8 carbonatoms or amino,

D - represents hydrogen, hydroxyl or

cycloalkyl having 3 to 8 carbon atoms

represents straight-chain or branched alkyl each having up to 12 carbonatoms, which is optionally substituted by halogen, hydroxyl or alkoxyhaving up to 8 carbon atoms,

E - has the meaning mentioned above for A and is identical or differentto this, or

represents hydrogen or

represents cycloalkyl having 3 to 8 carbon atoms,

represents straight-chain or branched alkyl having up to 12 carbonatoms, which is optionally substituted by halogen, straight-chain orbranched alkenyl having up to 8 carbon atoms, aryl having 6 to 10 carbonatoms, by a 5- to 7-membered heterocycle having up to 4 heteroatoms fromthe series comprising nitrogen, oxygen or sulphur or by a group of theformula --NR¹ R², --OR⁴, --COR⁵ or --S(O)_(n) --R⁶, in which

R¹ and R² have the abovementioned meanings,

R⁴ - denotes hydrogen or

straight-chain or branched alkyl having up to 10 carbon atoms, which isoptionally substituted by hydroxyl, trialkylsilyl having up to 10 carbonatoms in the alkyl moiety, or halogen or aryl having 6 to 10 carbonatoms,

denotes trialkylsilyl having up to 10 carbon atoms or cycloalkyl having3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which may inturn be substituted by halogen, cyano, nitro or amino, or

denotes a group of the formula --COR⁷, in which

R⁷ - denotes straight-chain or branched alkyl having up to 8 carbonatoms, aryl having 6 to 10 carbon atoms or the group --NR¹ R², in which

R¹ and R² have the abovementioned meanings,

R⁵ - denotes hydrogen or straight-chain or branched alkyl having up to 8carbon atoms, which is optionally substituted by hydroxyl, phenyl,halogen or cyano,

denotes aryl having 6 to 10 carbon atoms, which may be substituted byhalogen, amino, hydroxyl, nitro or cyano, or

denotes a group of the formula --NR¹ R² or --OR⁴, in which

R¹, R² and R⁴ have the abovementioned meanings,

n - denotes a number 0 or 2,

R⁶ - denotes straight-chain or branched alkyl having up to 10 carbonatoms, in which may be substituted by halogen, hydroxyl, phenyl or agroup of the formula --NR¹ R², in which

R¹ and R² have the abovementioned meanings,

denotes aryl having 6 to 10 carbon atoms, which may be substituted byhalogen, hydroxyl, cyano, nitro or amino, or

denotes a group of the formula --NR¹ R², if n represents the number 2,in which

R¹ and R² have the abovementioned meanings, or

E - represents a group of the formula --NR¹ R² or --OR⁴, in which

R¹, R² and R⁴ have the abovementioned meanings,

Y and Z are identical or different and

represent a group of the formula ##STR3## or Y - represents athiocarbonyl group,

X - represents a group of the formula --CH₂ --CH₂ -- or --CH═CH--, and

R - represents a group of the formula ##STR4## in which R⁸ - denoteshydrogen or straight-chain or branched alkyl having up to 10 carbonatoms, and

R⁹ - denotes hydrogen or straight-chain or branched alkyl having up to10 carbon atoms, which may be substituted by phenyl, or

denotes aryl having 6 to 10 carbon atoms or a cation,

and their salts have now been found.

If R⁹ forms an ester radical with the carboxy group, then aphysiologically tolerable ester radical, which is easily hydrolyzed invivo to give a free carboxy group and a corresponding physiologicallytolerable alcohol, is preferably meant by this. These include, forexample, alkyl esters (C₁ to C₆) and aryl esters (C₇ to C₁₀), preferably(C₁ -C₄)-alkyl esters and benzyl esters. Moreover, the following esterradicals may be mentioned: methyl esters, ethyl esters, propyl estersand benzyl esters.

If R⁹ represents a cation, then a physiologically tolerable metal cationor ammonium cation is preferably meant. Preferred cations in thisconnection are alkali metal or alkaline earth metal cations such as, forexample, sodium, potassium, magnesium or calcium cations, and alsoaluminum or ammonium cations, and non-toxic substituted ammonium cationsof amines such as (C₁ -C₄)-dialkylamines, (C₁ -C₄)-trialkylamines,procaine, dibenzylamine, N,N'-dibenzylethylenediamine,N-benzyl-β-phenylethylamine, N-methylmorpholine or N-ethylmorpholine,1-ephenamine, dihydroabietylamine,N,N'-bis-dihydroabietylethylenediamine, N-lower alkylpiperidine andother amines which may be used for the formation of salts.

Surprisingly, the substituted pyrido(2,3-d)pyrimidines according to theinvention show a superior inhibitory action on HMG-CoA reductase(3-hydroxy-3-methyl-glutaryl-coenzyme A reductase).

In the context of the general formula (I), compounds of the generalformula (Ia) and (Ib) ##STR5## in which A, B, D, E, X, Y, Z and R havethe abovementioned meanings, are preferred.

Preferred compounds are those of the general formula (Ia) and (Ib), inwhich

A - represents thienyl, furyl, pyridyl or pyrimidyl, each of which isoptionally monosubstituted to trisubstituted by identical or differentsubstituents from the series comprising fluorine, chlorine, bromine,hydroxyl, trifluoromethyl, straight-chain or branched alkyl, alkoxy oralkoxycarbonyl each having up to 6 carbon atoms, phenyl, or by a groupof the formula --NR¹ R², in which

R¹ and R² are identical or different and

denote hydrogen, phenyl, phenylsulphonyl, straight-chain or branchedalkyl or alkylsulphonyl having up to 6 carbon atoms, or benzyl orbenzylsulphonyl,

denote a group of the formula --COR³, in which

R³ -denotes straight-chain or branched alkyl or alkoxy having up to 6carbon atoms or phenyl, or

represents phenyl or naphthyl, which is optionally monosubstituted totetrasubstituted by identical or different straight-chain or branchedsubstituents from the series comprising alkyl, alkoxy or alkoxycarbonyleach having up to 8 carbon atoms, which may in turn be substituted bytrifluoromethyl, hydroxyl, alkoxyl having up to 4 carbon atoms, phenylor phenoxy, or is substituted by phenyl, phenoxy, phenylthio,phenylsulphonyl, fluorine, chlorine, bromine, nitro, cyano,trifluoromethyl, benzyloxy or by a group of the formula --NR¹ R², inwhich

R¹ and R² have the abovementioned meanings, or represents straight-chainor branched alkyl each having up to 6 carbon atoms

B - represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

represents trifluoromethyl or straight-chain or branched alkyl having upto 10 carbon atoms, which is optionally substituted by fluorine,chlorine, bromine, hydroxyl, cyano, azido, trifluoromethyl, methylthio,methylsulphonyl, alkoxy having up to 6 carbon atoms or by phenyl,phenyloxy or phenylthio, where the phenyl radicals may bemonosubstituted or disubstituted by identical or different substituentsfrom the series comprising fluorine, chlorine, bromine, cyano,trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl,alkoxy, alkylthio or alkylsulphonyl each having up to 6 carbon atoms, oris substituted by a group of the formula --NR¹ R² or --COR³, in which

R¹, R² and R³ have the abovementioned meanings, or represents phenyl,which is optionally substituted by fluorine or chlorine,

D - represents hydrogen, hydroxyl or

represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

represents straight-chain or branched alkyl having up to 10 carbonatoms, which is optionally substituted by fluorine, chlorine, bromine,hydroxyl or alkoxy having up to 6 carbon atoms,

E - has the meaning mentioned above for A and is identical or differentto this, or

represents hydrogen or

represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

represents straight-chain or branched alkyl having up to 10 carbonatoms, which is optionally substituted by fluorine, chlorine, bromine,straight-chain or branched alkenyl having up to 6 carbon atoms, phenyl,pyrimidyl, pyrrolyl, pyrrolidinyl, furyl or thiazolyl, or by a group ofthe formula --NR¹ R², --OR⁴, --COR⁵ or --S(O)_(n) --R⁶, in which

R¹ and R² have the abovementioned meanings,

R⁴ - denotes hydrogen or

straight-chain or branched alkyl having up to 8 carbon atoms, which isoptionally substituted by hydroxyl, fluorine, chorine, bromine or byphenyl, or

denotes a group of the formula --COR⁷, in which

R⁷ - denotes straight-chain or branched alkyl having up to 6 carbonatoms, phenyl or a group of the formula --NR¹ R², in which

R¹ and R² have the abovementioned meanings,

R⁵ - denotes hydrogen, or straight-chain or branched alkyl having up to6 carbon atoms, which is optionally substituted by hydroxyl, phenyl,fluorine, chlorine, bromine or cyano,

denotes phenyl which may in turn be substituted by fluorine, chlorine,bromine, amino, hydroxyl, nitro or cyano, or

denotes a group of the formula --NR¹ R² or --OR⁴, in which

R¹, R² and R⁴ have the abovementioned meanings,

n - denotes a number 0 or 2,

R⁶ - denotes straight-chain or branched alkyl having up to 8 carbonatoms or,

phenyl which may be substituted by fluorine, chlorine, bromine,hydroxyl, cyano, nitro or amino, or

may denote a group of the formula --NR¹ R², if n represents the number2, in which

R¹ and R² have the abovementioned meanings, or

E - represents a group of the formula --NR¹ R² or --OR⁴, in which

R¹, R² and R⁴ have the abovementioned meanings,

Y and Z are identical or different and represent a group of the formula##STR6## or Y - represents a thiocarbonyl group,

X - represents a group of the formula --CH₂ --CH₂ -- or --CH═CH-- and

R - represents a group of the formula ##STR7## in which R⁸ - denoteshydrogen or straight-chain or branched alkyl having up to 8 carbonatoms, and

R⁹ - denotes hydrogen or straight-chain or branched alkyl having up to 8carbon atoms or benzyl, or

denotes phenyl or a cation

and their salts.

Particularly preferred compounds are those of the general formulae (Ia)and (Ib), in which

A - represents thienyl, furyl or pyridyl, which is optionallymonosubstituted or disubstituted by identical or different substituentsfrom the series comprising fluorine, chlorine, bromine, hydroxyl,trifluoromethyl, methyl, ethyl, methoxy, ethoxy or phenyl, or by a groupof the formula --NR¹ R², in which

R¹ and R² are identical or different and denote hydrogen, phenyl, orstraight-chain or branched alkyl having up to 4 carbon atoms,

represents phenyl which is optionally monosubstituted to trisubstitutedby identical or different substituents from the series comprisingstraight-chain or branched alkyl or alkoxy each having up to 6 carbonatoms, which may in turn be substituted by trifluoromethyl, hydroxyl,methoxy, ethoxy, propoxy, phenyl or phenoxy, or is substituted byphenyl, phenoxy, fluorine or chlorine, or

represents straight-chain or branched alkyl having up to 4 carbon atoms

B - represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

represents methyl, ethyl, propyl, isopropyl, butyl, tert. butyl ortrifluoromethyl,

represents phenyl, which is optionally substituted by fluorine,

D - represents hydrogen or

represents cyclopropyl, cyclopentyl or cyclohexyl,

represents methyl, ethyl, propyl, isopropyl, butyl or tert. butyl,

E - has the meaning mentioned above for A and is identical or differentto this, or

represents hydrogen, or

represents cyclopropyl, cyclopentyl or cyclohexyl,

represents straight-chain or branched alkyl having up to 8 carbon atoms,which is optionally substituted by fluorine, chlorine, straight-chain orbranched alkenyl having up to 4 carbon atoms, phenyl or furyl, or

is substituted by a group of the formula --NR¹ R² or --OR⁴, in which

R¹ and R² have the abovementioned meanings,

R⁴ - denotes hydrogen or

straight-chain or branched alkyl having up to 6 carbon atoms, which isoptionally substituted by hydroxyl or by phenyl, or

E - represents a group of the formula --NR¹ R², in which

R¹ and R² have the abovementioned meanings,

Y and Z are identical or different and represent a group of the formula##STR8## or Y - represents a thiocarbonyl group,

X - represents a group --CH═CH-- and

R - represents a group of the formula ##STR9## in which R⁸ - denoteshydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.butyl and p2 R⁹ - denotes hydrogen, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert. butyl or benzyl, or

denotes a sodium, potassium, calcium, magnesium or ammonium ion,

and their salts.

The substituted pyrido(2,3-d)pyrimidines of the general formula (I)according to the invention have several asymmetric carbon atoms and cantherefore exist in various stereochemical forms. The invention relatesboth to the individual isomers and to their mixtures.

Depending on the meaning of the group X or the radical R, differentstereoisomers result, which are intended to be illustrated in moredetail in the following:

a) if the group -X- represents a group of the formula --CH═CH--, thecompounds according to the invention can exist in two stereoisomericforms which can have the E configuration (II) or Z configuration (III)on the double bond: ##STR10## (A, B, D, E, Y, Z and R have theabovementioned meanings).

Preferred compounds of the general formula (I) are those which have theE configuration (II).

b) If the radical -R- represents a group of the formula ##STR11## thecompounds of the general formula (I) have at least two asymmetric carbonatoms, namely the two carbon atoms to which the hydroxyl groups arebonded. Depending on the relative position of these hydroxyl groups toone another, the compounds according to the invention may be present inthe erythro configuration (IV) or in the threo configuration (V).##STR12## In turn, two enantiomers each exist both of the compounds inthe erythro and in the threo configuration, namely the 3R,5S-isomer orthe 3S,5R-isomer (erythro form) and the 3R,5R-isomer and 3S,5S-isomer(threo form).

In this connection, the isomers in the erythro configuration arepreferred, particularly preferably the 3R,5S-isomer and the3R,5S-3S,5R-racemate.

c) If the radical -R- represents a group of the formula ##STR13## thesubstituted pyrido(2,3-d)pyrimidines have at least two asymmetric carbonatoms, namely the carbon atom to which the hydroxyl group is bonded, andthe carbon atom to which the radical of the formula ##STR14## is bonded.Depending on the position of the hydroxyl group to the free valency onthe lactone ring, the substituted pyrido(2,3-d)pyrimidines may bepresent as cis-lactones (VI) or as trans-lactones (VII). ##STR15##

In turn, two isomers each exist of the cis-lactone and thetrans-lactone, namely the 4R,6R-isomer or the 4S,6S-isomer(cis-lactone), and the 4R,6S-isomer or 4S,6R-isomer (trans-lactone).Preferred isomers are the trans-lactones. The 4R,6S-isomer (trans) andthe 4R,6S-4S,6R-racemate are particularly preferred in this connection.

For example, the following isomeric forms of the substitutedpyrido(2,3-d)pyrimidines may be mentioned: ##STR16##

In addition, a process for the preparation of the substitutedpyrido(2,3-d)pyrimidines of the general formula (I) ##STR17## in whichA, B, D, E, X, Y, Z and R have the abovementioned meanings,

has been found which is characterized in that ketones of the generalformula (VIII) ##STR18## in which A, B, D, E, Y and Z have theabovementioned meanings, and

R¹⁰ - represents alkyl having up to 6 carbon atoms, are reduced,

in the case of the preparation of the acids the esters are hydrolyzed,

in the case of the preparation of the lactones the carboxylic acids arecyclized,

in the case of the preparation of the salts either the esters or thelactones are hydrolyzed,

in the case of the preparation of the ethylene compounds (X═--CH₂ --CH₂--) the ethene compounds (X═--CH═CH--) are hydrogenated according tocustomary methods, and, if appropriate, isomers are separated.

The process according to the invention can be illustrated by thefollowing equation: ##STR19##

The reduction can be carried out using the customary reducing agents,preferably those which are suitable for the reduction of ketones tohydroxy compounds. Reduction using metal hydrides or complex metalhydrides in inert solvents is particularly suitable in this connection,if appropriate in the presence of a trialkylborane. Preferably, thereduction is carried out using complex metal hydrides such as, forexample, lithium borohydride, sodium borohydride, potassium borhydride,zinc borohydride, lithium trialkylborohydrides, sodiumtrialkylborohydrides, sodium cyanoborohydride or lithium aluminumhydride. Very particularly preferably, the reduction is carried outusing sodium borohydride in the presence of triethylborane and methanol.

Suitable solvents in this connection are the customary organic solventswhich do not change under the reaction conditions. These preferablyinclude ethers such as, for example, diethyl ether, dioxane,tetrahydrofuran or dimethoxyethane, or halogenated hydrocarbons such as,for example, dichloromethane, trichloromethane, tetrachloromethane,1,2-dichloroethane, or hydrocarbons such as, for example, benzene,toluene or xylene. It is likewise possible to employ mixtures of thesolvents mentioned.

Particularly preferably, the reduction of the ketone group to thehydroxy group is carried out under conditions in which the customaryfunctional groups such as, for example, the alkoxycarbonyl group do notchange. The use of sodium borohydride as a reducing agent in thepresence of triethylborane and methanol in inert solvents such as,preferably, ethers is particularly preferable for this purpose.

The reduction is in general carried out in a temperature range from -80°C. to +30° C., preferably from -78° C. to 0° C.

The process according to the invention is in general carried out atatmospheric pressure. However, it is also possible to carry out theprocess at reduced pressure or at elevated pressure (for example in arange from 0.5 to 5 bar).

In general, the reducing agent is employed in an amount from 1 to 2moles, preferably from 1 to 1.5 moles, relative to 1 mole of the ketocompound.

Under the abovementioned reaction conditions, the carbonyl group is ingeneral reduced to the hydroxyl group without reduction of the doublebond to a single bond taking place.

In order to prepare compounds of the general formula (I), in which Xrepresents an ethylene grouping, the reduction of the ketones (III) canbe carried out under those conditions under which both the carbonylgroup and the double bond are reduced.

Moreover, it is also possible to carry out the reduction of the carbonylgroup and the reduction of the double bond in two separate steps.

The carboxylic acids in the context of the general formula (I)correspond to the formula (Ic) ##STR20## in which A, B, D, E, X, Y, Zand R⁸ have the abovementioned meanings,

The carboxylic acid esters in the context of the general formula (I)correspond to the formula (Id) ##STR21## in which A, B, D, E, X, Y, Zand R⁸ have the abovementioned meanings, and

R¹⁰ - represents alkyl having up to 6 carbon atoms.

The salts of the compounds in the context of the general formula (I)according to the invention correspond to the formula (Ie) ##STR22## inwhich A, B, D, E, X, Y, Z and R⁸ have the abovementioned meanings, and

Mn⁺ represents a cation, where n indicates the valency.

The lactones in the context of the general formula (I) correspond to theformula (If) ##STR23## in which A, B, D, E, X, Y, Z and R⁸ have theabovementioned meanings,

In order to prepare the carboxylic acids of the general formula (Ic)according to the invention, the carboxylic acid esters of the generalformula (Id) or the lactones of the general formula (If) are in generalhydrolyzed according to customary methods. Hydrolysis is in generalcarried out by treating the esters or the lactones in inert solventswith customary bases, the salts of the general formula (Ie) initiallyresulting, which can subsequently be converted in a second step bytreating with acid into the free acids of the general formula (Ic).

Suitable bases for hydrolysis are the customary inorganic bases. Thesepreferably include alkali metal hydroxides or alkaline earth metalhydroxides such as, for example, sodium hydroxide, potassium hydroxideor barium hydroxide, or alkali metal carbonates such as sodium carbonateor potassium carbonate or sodium hydrogen carbonate, or alkali metalalkoxides such as sodium ethoxide, sodium methoxide, potassiummethoxide, potassium ethoxide or potassium tert. butoxide. Sodiumhydroxide or potassium are particularly preferably employed.

Suitable solvents for hydrolysis are water or the organic solventscustomary for hydrolysis. These preferably include alcohols such asmethanol, ethanol, propanol, isopropanol or butanol, or ethers such astetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide.It is also possible to employ mixtures of the solvents mentioned.Particularly preferably, alcohols such as methanol, ethanol, propanol orisopropanol or a mixture of tetrahydrofuran and water are used.

The hydrolysis is in general carried out in a temperature range from 0°C. to +100° C., preferably from +20° C. to +80° C.

In general, the hydrolysis is carried out at atmospheric pressure.However, it is also possible to work at reduced pressure or elevatedpressure (for example from 0.5 to 5 bar).

When carrying out the hydrolysis, the base is in general employed in anamount from 1 to 3 moles, preferably from 1 to 1.5 moles, relative to 1mole of the ester or the lactone. Equimolar amounts of the reactants areparticularly preferably used.

When carrying out the reaction, the salts of the compounds (Ie)according to the invention are formed in the first step as intermediateswhich can be isolated. The acids (Ic) according to the invention areobtained by treating the salts (Ie) with customary inorganic acids.These preferably include mineral acids such as, for example,hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid.It has proved advantageous in this connection in the preparation of thecarboxylic acids (Ic) to acidify the basic reaction mixture from thehydrolysis in a second step without isolation of the salts. The acidscan then be isolated in a customary manner.

In order to prepare the lactones of the formula (If) according to theinvention, the carboxylic acids (Ic) according to the invention are ingeneral cyclized according to the customary methods, for example byheating the corresponding acid in inert organic solvents, if appropriatein the presence of molecular sieve.

Suitable solvents in this connection are hydrocarbons such as benzene,toluene, xylene, mineral oil fractions, or tetralin or diglyme ortriglyme. Benzene, toluene or xylene are preferably employed. It is alsopossible to employ mixtures of the solvents mentioned. Hydrocarbons, inparticular toluene, in the presence of molecular sieve are particularlypreferably used.

Cyclization is in general carried out in a temperature range from -40°C. to +200° C., preferably from -25° C. to +110° C.

Cyclization is in general carried out at atmospheric pressure, but it isalso possible to carry out the process at reduced pressure or atelevated pressure (for example in a range from 0.5 to 5 bar).

Moreover, the cyclization is also carried out in inert organic solvents,with the aid of cyclizing or dehydrating agents. Carbodiimides arepreferably used as dehydrating agents in this connection.N,N'-dicyclohexylcarbodiimide paratoluenesulphonate,N-cyclohexyl-N'-[2-(N"-methylmorpholinium)ethyl]carbodiimide orN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride arepreferably employed as carbodiimides.

Suitable solvents in this connection are the customary organic solvents.These preferably include ethers such as diethyl ether, tetrahydrofuranor dioxane, or chlorinated hydrocarbons such as methylene chloride,chloroform or carbon tetrachloride, or hydrocarbons such as benzene,toluene, xylene or mineral oil fractions. Chlorinated hydrocarbons suchas, for example, methylene chloride, chloroform or carbon tetrachloride,or hydrocarbons such as benzene, toluene, xylene or mineral oilfractions are particularly preferred. Chlorinated hydrocarbons such as,for example, methylene chloride, chloroform or carbon tetrachloride areparticularly preferably employed.

The reaction is in general carried out in a temperature range from 0° C.to +80° C., preferably from +10° C. to +50° C.

When carrying out the cyclization, it has proved advantageous to employthe cyclization method with the aid of carbodiimides as dehydratingagents.

The resolution of the isomers into the stereoisomerically uniformconstituents is in general carried out by customary methods such as aredescribed, for example, by E. L. Eliel, Stereochemistry of CarbonCompounds, McGraw Hill, 1962. Resolution of the isomers in the racemicester step is preferred in this connection. The racemic mixtures of thetrans-lactones (VII) is particularly preferably converted in this caseby treating either with D-(+)- or L-(-)-α-methylbenzylamine by customarymethods into the diastereomeric dihydroxyamides (Ig) ##STR24## which canthen be resolved into the individual diastereomers as is customary bychromatography or crystallization. Subsequent hydrolysis of the purediastereomeric amides by customary methods, for example by treating thediastereomeric amides with inorganic bases such as sodium hydroxide orpotassium hydroxide in water and/or organic solvents such as alcohols,for example methanol, ethanol, propanol or isopropanol, gives thecorresponding enantiomerically pure dihydroxy acids (Ic) which can beconverted into the enantiomerically pure lactones by cyclization asdescribed above. In general, it is true for the preparation of thecompounds of the general formula (I) according to the invention inenantiomerically pure form that the configuration of the final productsaccording to the methods described above is dependent on theconfiguration of the starting substances.

The resolution of isomers is intended to be illustrated by way ofexample in the following scheme: ##STR25##

The ketones (VIII) employed as starting substances are new.

A process for the preparation of the ketones of the general formula(VIII) according to the invention ##STR26## in which A, B, D, E, Y, Zand R¹⁰ have the abovementioned meanings, has been found which ischaracterized in that aldehydes of the general formula (IX) ##STR27## inwhich A, B, D, E, Y and Z have the abovementioned meanings, are reactedin inert solvents with acetoacetic esters of the general formula (X)##STR28## in which R¹⁰ has the abovementioned meaning, in the presenceof bases.

The process according to the invention can be illustrated, for example,by the following equation: ##STR29##

Suitable bases in this connection are the customary strong basiccompounds. These preferably include organolithium compounds such as, forexample, N-butyllithium, sec. butyllithium, tert. butyllithium orphenyllithium, or amides such as, for example, lithium diisopropylamide,sodium amide or potassium amide, or lithium hexamethyldisilylamide, oralkali metal hydrides such as sodium hydride or potassium hydride. It islikewise possible to employ mixtures of the bases mentioned.N-butyllithium or sodium hydride or a mixture thereof is particularlypreferably employed.

Additions of metal halides such as, for example, magnesium chloride,zinc chloride or zinc bromide may be advantageous. The addition of zinchalides is particularly preferred.

Suitable solvents in this connection are the customary organic solventswhich do not change under the reaction conditions. These preferablyinclude ethers such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane, or hydrocarbons such as benzene, toluene, xylene,cyclohexane, hexane or mineral oil fractions. It is likewise possible toemploy mixtures of the solvents mentioned. Ethers such as diethyl etheror tetrahydrofuran are particularly preferably used.

The reaction is in general carried out in a temperature range from -80°C. to +50° C., preferably from -20° C. to room temperature.

The process is in general carried out at atmospheric pressure, but it isalso possible to carry out the process at reduced pressure or elevatedpressure, for example in a range from 0.5 to 5 bar.

When carrying out the process, the acetoacetic ester is in generalemployed in an amount from 1 to 3, preferably from 1 to 2, moles,relative to 1 mole of the aldehyde.

The acetoacetic esters of the formula (X) employed as startingsubstances are known or can be prepared by known methods [Beilstein'sHandbuch der organischen Chemie (Beilstein's Handbook of OrganicChemistry) III, 62; 438].

Examples of acetoacetic esters for the process according to theinvention which may be mentioned are: methyl acetoacetate, ethylacetoacetate, propyl acetoacetate and isopropyl acetoacetate.

The preparation of the aldehydes of the general formula (IX) employed asstarting substances is intended to be illustrated below by way ofexample for the 1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidines of the type(Ia). ##STR30##

In this connection, the 1,2,3,4,5,8-hexahydropyrido(2,3-d)pyrimidines ofthe general formula (XI), in which R¹¹ stands for an alkyl radicalhaving up to 4 carbon atoms, are oxidized in suitable solvents usingsuitable oxidizing agents as in the first step [A]. Preferably1,2,3,4-hexahydro-pyrido(2,3-d)pyrimidines in chlorinated hydrocarbonssuch as, for example, methylene chloride, are oxidized with2,3-dichloro-4,5-dicyano-p-benzoquinone at room temperature, or withchromium trioxide in glacial acetic acid at elevated temperatures,preferably at reflux temperature, to give the1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidines (XII). In the second step[B], the 1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidines (XII) are reducedin inert solvents such as ethers, for example diethyl ether,tetrahydrofuran or dioxane, or in hydrocarbons, for example benzene ortoluene, preferably in tetrahydrofuran or toluene, using metal hydridesas reducing agents, for example lithium aluminum hydride, sodiumcyanoborohydride, sodium aluminum hydride, diisobutylaluminum hydride orsodium bis-(2-methoxyethoxy)-dihydroaluminate, in temperature rangesfrom -70° C. to +100° C., preferably from -70° C. to room temperature,or from room temperature to 70 ° C. depending on the reducing agent usedto give the hydroxymethyl compounds (XIII). The reduction is preferablycarried out using diisobutylaluminum hydride in tetrahydrofuran in atemperature range from -78° C. to room temperature. In the third step[C], the hydroxymethyl compounds (XIII) are oxidized by customarymethods to give the aldehydes (XIV). The oxidation can be carried out,for example, with pyridinium chlorochromate, if appropriate in thepresence of alumina, in inert solvents such as chlorinated hydrocarbonsor ethers, preferably methylene chloride or tetrahydrofuran, at roomtemperature or with trifluoroacetic anhydride and dimethyl sulphoxide(Swern oxidation) or else by other methods customary for the oxidationof hydroxymethyl compounds to aldehydes. In the fourth step [D], thealdehydes (XIV) are converted into the compounds (IX) by reacting withdiethyl 2-(cyclohexylamino)-vinyl-phosphonate or with1,3-dioxane-2-yl-methyl-triphenylphosphonium bromide in inert solventssuch as ethers or dimethylformamide, preferably in tetrahydrofuran inthe presence of sodium hydride or sodium ethoxide, in a temperaturerange from -20° C. to +30° C., preferably from -5° C. to roomtemperature.

The compounds of the general formula (IX), in which D has theabovementioned meaning, but does not represent hydrogen, can be preparedby alkylating compounds of the general formula (IXa) ##STR31## in whichA, B, E, Y and Z have the abovementioned meanings, to introduce D, usingalkyl halides, preferably alkyl iodide, for example methyl iodide, inthe presence of the abovementioned bases, preferably sodium hydride orusing activated olefins, such as, for example, acrylonitrile in theabovementioned inert solvents, preferably tetrahydrofuran.

The compounds of the general formula (XI) employed as startingsubstances are known per se or can be prepared by customary methods[compare German Offenlegungsschrift DE 2,738,153, U.S. Pat. No.4,596,805; V. Papesch, E. F. Schroeder, J. Org. Chem. 13, 1879, (1951);T. Kishihawe, H. Yuhi, Chem. Pharm. volume 14, 1365-1370 (1966)].

The starting compounds of the general formulae (XII), (XIII) and (XIV)are known per se or can be prepared by customary methods [Chem. Ber. 101(2), 512-521; J. Heterocycl. Chem., 22 (2), 345-347; Khim. Geterosikl.Soedin., (6), 834-837; Farmaco, Ed. Sci. 37 (4), 247-258].

The compounds of the general formula (I) according to the inventionpossess useful pharmacological properties and can be employed inmedicaments. In particular, they are inhibitors of3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductanse and, as aresult of this, inhibitors of cholesterol biosynthesis. They cantherefore be employed for the treatment of hyperlipoproteinaemia,lipoproteinaemia or atherosclerosis. The active substances according tothe invention additionally cause a lowering of the cholesterol contentin the blood.

The enzyme activity determination was carried out as modified by G. C.Ness et al., Archives of Biochemistry and Biphysics 197, 493-499 [1979].Male Rico rats (body weight 300-400 g) were treated for 11 days withaltromin powdered feed to which 40 g of cholestyramine/kg of feed hadbeen added. After description, the livers were removed from the animalsand placed on ice. The livers were comminuted and homogenized 3 times in3 volumes of 0.1 m sucrose, 0.05 m KCl, 0.04 m K_(x) H_(y) phosphate,0.03 m ethylenediaminetetraacetic acid, 0.002 m dithiothreitol [SPE]buffer pH 7.2 in a Potter-Elvejem homogenizer. The mixture was thencentrifuged at 15,000 g for 15 minutes and the sediment was discarded.The supernatant was sedimented at 100,000 g for 75 minutes. The pelletwas taken up in 1/4 volumes of SPE buffer, homogenized once more andthen centrifuged again at 100,000 g for 60 minutes. The pellet was takenup using a 5-fold amount of its volume of SPE buffer, homogenized andfrozen and stored at -78° C. (=enzyme solution).

For testing, the test compounds (or mevinolin as a reference substance)were dissolved in diemthylformamide with the addition of 5 vol.-% of 1 NNaOH and, using 10 μl, employed in the enzyme test in variousconcentrations. The test was started after preincubation of thecompounds with the enzyme at 37° C. for 20 minutes. The test batch was0.380 ml and contained 4 μmol of glucose-6-phosphate, 1.1 mg of bovineserum albumin, 2.1 μmol of dithiothreitol, 0.35 μmol of NADP, 1 unit ofglucose-6-phosphate dehydrogenase, 35 μmol of K_(x) H_(y) phosphate pH7.2, 20 μl of enzyme preparation and 56 nmol of3-hydroxy-3-methyl-glutaryl-coenzyme A (glutaryl-3-¹⁴ C) 100,000 dpm.

After incubating for 60 minutes at 37° C., the batch was centrifuged and600 μl of the supernatant was applied to a 0.7×4 cm column packed with a5-chloride 100-200 mesh (anion exchanger). The column was subsequentlywashed with 2 ml of distilled water and 3 ml of Aquasol were added torunnings plus washing water and counted in an LKB scintillation counter.IC₅₀ values were determined by intrapolation by plotting the percentageinhibition against the concentration of the compound in the test. Inorder to determine the relative inhibitory potency, the IC₅₀ value ofthe reference substance mevinolin was set at 1 and compared with thesimultaneously determined IC₅₀ value of the test compound.

    ______________________________________                                        Relative in vitro activities                                                                relative activity                                               Example No.   (mevinolin = 1)                                                 ______________________________________                                         8            2                                                               16            6                                                               ______________________________________                                    

The new active substances can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginsert, non-toxic, pharmaceutically suitable excipients or solvents. Inthis connection, the therapeutically active compound should in each casebe present in a concentration of about 0.5 to 98% by weight, preferably1 to 90% by weight, of the total mixture, i.e. in amounts which aresufficient in order to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the activecompounds with solvents, and/or excipients, if appropriate usingemulsifiers and/or dispersants, where, for example, in the case of theuse of water as a diluent, if appropriate organic solvents can also beused as auxiliary solvents.

Examples of auxiliaries which may be mentioned are:

water, non-toxic organic solvents, such as paraffins (for examplemineral oil fractions), vegetable oils (for example groundnut/sesameoil), alcohols (for example: ethyl alcohol, glycerol), excipients, suchas, for example, ground natural minerals (for example, kaolins, clays,talc, chalk), ground synthetic minerals (for example highly dispersesilica, silicates), sugars (for example sucrose, lactose and dextrose),emulsifiers (for example polyoxyethylene fatty acid esters,polyoxyethylene fatty alcohol ethers, alkyl sulphonates and arylsulphonates), dispersing agents (for example ligninsulphate wasteliquors, methylcellulose, starch and polyvinylpyrrolidone) andlubricants (for example magnesium stearate, talc, stearic acid andsodium lauryl sulphate).

Administration is carried out in a customary manner, preferably orally,parenterally, perlingually or intravenously. In the case of oraladministration, tablets may of course also contain additions, such assodium citrate, calcium carbonate and dicalcium phosphate together withvarious additives, such as starch, preferably potato starch, gelatin andthe like in addition to the excipients mentioned. Furthermore,lubricants, such as magnesium stearate, sodium lauryl sulphate and talccan additionally be used for tableting. In the case of aqueoussuspensions, various flavor enhancers or colorants may be added to theactive compounds in addition to the abovementioned auxiliaries.

In the case of paraneteral administration, solutions of the activecompounds using suitable liquid excipients may be employed.

In general, it has proved advantageous on intravenous administration toadminister amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to0.5 mg/kg of body weight to attain effective results, and on oraladministration the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to10 mg/kg of body weight.

In spite of this it may be necessary to deviate from the amountsmentioned, depending on the body weights or the type of administrationroute, on individual behaviour towards the medicament, the manner of itsformulation and the point in time or interval at which administrationtakes place.

Thus in some cases it may be sufficient to manage with less than theminimum amount previously mentioned, whereas in other cases the upperlimit mentioned must be exceeded. In the case of the administration oflarger amounts, it may be advisable to divide these into a number ofindividual doses over the day.

Preparation examples EXAMPLE 1E,Z-2-Ethoxycarbonyl-1-(4-fluorophenyl)-4-methyl-pent-1-en-3-one##STR32##

A solution of 20 ml (0.2 mol) of piperidine and 12 ml (0.21 mmol) ofacetic acid in 200 ml of isopropanol is added to 554 g (3.5 mol) ofethyl isobutyryl acetate and 434 g (3.5 mol) of 4-fluorobenzaldehyde in1.8 l of isopropanol. The mixture is stirred at room temperature for 1day and concentrated in vacuo, and the residue is distilled in a highvacuum.

Yield: 796 g (86% of theory) of yellowish oil.

b.p.: 135°-140° C. (0.2 mbar).

EXAMPLE 21-Butyl-6-ethoxycarbonyl-5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4,5,8-hexahydro-pyrido(2,3-d)pyrimidine##STR33##

91.6 g (0.5 mol) of 6-amino-1-butyl-uracil and 145.4 g (0.55 mol) of thecompound from Example 1 are heated at reflux overnight in 750 ml ofisopropanol. A further 39.6 g (0.15 mol) of the compound from Example 1are added and the mixture is boiled for a further day. The precipitatewhich deposits is filtered off with suction and subsequently washed witha little isopropanol.

Yield: 143.9 g (67% of theory) of colorless crystals.

m.p.: 214° C. (from methanol).

EXAMPLE 31-Butyl-6-ethoxycarbonyl-5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR34##

11.35 g (50 mmol) of 2,3-dichloro-4,5-dicyanobenzoquinone are added to amixture of 21.5 g (50 mmol) of the compound from Example 2 in 800 ml ofdichloromethane and the mixture is stirred at room temperature for 1 h.The solution is filtered from a beige precipitate, the filtrate iswashed four times with water, the organic phase is dried over sodiumsulphate, filtered through a thin layer of active carbon and thefiltrate is concentrated in vacuo. The residue is crystallized fromether/petroleum ether.

Yield: 20.1 g (94% of theory) of colorless crystals.

m.p.: 129° C.

EXAMPLE 41-Butyl-5-(4-fluorophenyl)-6-hydroxymethyl-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR35##

135 ml of a 1 molar solution of diisobutylaluminum hydride in tolueneare slowly added under argon to a suspension of 19.2 g (45 mmol) of thecompound from Example 3 in 400 ml of toluene at -75° C., which leads toa clear solution. After 1 hour, a further 30 ml of dibutylaluminumhydride solution are added at the same temperature, the mixture isstirred for a further hour and then allowed to warm to room temperature,400 ml of water and 200 ml of ethyl acetate being added cautiously from-30° C. The mixture is filtered off with suction through kieselguhr andsubsequently washed with ethyl acetate. After phase separation, theaqueous phase is extracted with ethyl acetate, and the combined organicphases are washed with sodium chloride solution, dried over sodiumsulphate and concentrated in vacuo. The residue is chromatographed in acolumn (φ 6 cm) on 500 g of 230-400 mesh silica gel using petroleumether/ethyl acetate (2:1).

Yield: 11.8 g (68% of theory) of colorless crystals.

m.p.: 99° C. (from ether/petroleum ether).

EXAMPLE 51-Butyl-5-(4-fluorophenyl)-6-formyl-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR36##

8.5 g (22 mmol) of the compound from Example 4 are dissolved in 220 mlof dichloromethane, 4.5 g of neutral alumina and 9.5 g (44 mmol) ofpyridinium chlorochromate are added and the mixture is stirred at roomtemperature for 1 h. The mixture is filtered through a silica gel bed,without sucking dry, and subsequently washed with dichloromethane, andthe filtrate is concentrated to dryness in vacuo. The residue ischromatographed on 150 g of 230-400 mesh silica gel in a column (φ 4 cm)using petroleum ether/ethyl acetate 2:1.

Yield: 7.6 g (90% of theory) of colorless solid.

m.p.: 179° C.

EXAMPLE 6(E)-3-[1-Butyl-5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]prop-2-enal##STR37##

A solution of 1.15 g (4.4 mol) of diethyl2-(cyclohexylamino)-vinyl-phosphonate in 15 ml of tetrahydrofuran isadded dropwise in the course of 10 min at 0°-5° C. under argon to asuspension of 0.25 g (8.4 mmol) of 80% strength sodium hydride in 15 mlof anhydrous tetrahydrofuran. The mixture is stirred at 0° C. for 15min, a solution of 1.5 g (4 mmol) of the compound from Example 5 in 15ml of tetrahydrofuran is added dropwise at 0° C. in the course of 20min, and the mixture is stirred at room temperature for 1 h and underreflux for 20 min. The mixture is cooled, 50 ml of water are addedcautiously, the mixture is extracted twice with ethyl acetate, and thecombined organic phases are washed with sodium chloride solution andconcentrated in vacuo. The residue is heated under reflux with a mixtureof 25 ml of toluene, 35 ml of water and 2.6 g (36 mmol) of oxalic aciddihydrate for 1 h. The phases are separated, the aqueous phase isextracted with ethyl acetate, and the combined organic phases are washedwith sodium chloride solution, dried over magnesium sulphate andconcentrated in vacuo. The residue is crystallized from ether/petroleumether.

Yield: 1.0 g (61% of theory) of yellowish solid.

m.p.: 162° C.

EXAMPLE 7 Methyl(E)-7-[1-butyl-5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-5-hydroxy-3-oxo-hept-6-enoate##STR38##

0.7 g (6 mmol) of methyl acetoacetate are added dropwise at 0°-5° C. toa suspension of 0.2 g (6.6 mmol) of 80% strength sodium hydride in 8 mlof anhydrous tetrahydrofuran. After 15 min, 4.9 ml (8 mmol) of 15%strength butyllithium in hexane are added dropwise in the course of 10min and the mixture is kept at 0° C. for a further 15 min. 0.82 g (2mmol) of the compound from Example 6 and 10 ml of tetrahydrofuran arethen added and the mixture is stirred at 0°-5° C. for 1 h. 1.2 g (20mmol) of acetic acid in 20 ml of water are then added cautiously, themixture is extracted three times with ethyl acetate, and the organicphase is washed with sodium chloride solution, dried over sodiumsulphate and concentrated in vacuo. The residue is chromatographed on 40g of 230-400 mesh silica gel (φ 3 cm) using petroleum/ethyl acetate(2:1) to (1:3).

Yield: 0.14 g (13% of theory) of yellow oil.

R_(f) =0.3 (petroleum ether/ethyl acetate 1:1).

EXAMPLE 8 Methylerythro-(E)-7-[1-butyl-5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-terahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoate##STR39##

0.29 ml of a 1 molar solution of triethylborane in tetrahydrofuran isadded to a solution of 126 mg (0.24 mmol) of the compound from Example 7in 4 ml of anhydrous terahydrofuran and air is blown through thesolution for 5 min. 11.4 mg (0.3 mmol) of sodium borohydride are addedat -78° C., then 0.5 ml of methanol is added dropwise and the mixture iskept at -78° C. to -75° C. for 1 h. It is then allowed to warm to roomtemperature, 1 ml of 30% strength hydrogen peroxide and 20 ml of waterbeing added at -30° C. The mixture is extracted four times with ethylacetate, and the combined organic phases are washed with sodium chloridesolution, dried over sodium sulphate and concentrated. The residue ischromatographed on 15 g of silica gel (230-400 mesh) in a column (φ 2cm) using petroleum ether/ethyl acetate (1:1).

Yield: 52 mg (41% theory) of colorless solid.

m.p.: 171° C.

EXAMPLE 9Erythro-(E)-7-[1-butyl-5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enecarboxylic acid sodium salt ##STR40##

A solution of 27 mg (0.05 mmol) of the compound from Example 8 in 1 mlof tetrahydrofuran is stirred with 0.5 ml (0.05 mmol) of a 0.1 molarsodium hydroxide solution at room temperature for 2 h. The mixture isconcentrated and dried over phosphorus pentoxide in vacuo.

Yield: 22 mg (82% of theory) of colorless solid.

FAB-MS: 536 (M+H), 558 (M+Na).

EXAMPLE 106-Ethoxycarbonyl-5-(4-fluorophenyl)-7-isopropyl-1-methyl-2,4-dioxo-1,2,3,4,5,8-hexahydro-pyrido(2,3-d)pyrimidine##STR41##

39.5 g (0.28 mol) of 6-amino-1-methyl-uracil and 147.8 g (0.56 mol) ofthe compound from Example 1 are heated to 180° C. for 4 h. A further73.9 g (0.28 mol) of the compound from Example 1 are then added and themixture is heated again for 4 h. After cooling, the mixture is stirredthoroughly with 400 ml of methanol and the precipitate is filtered offwith suction.

Yield: 78.2 g (72% of theory) of yellowish solid.

m.p.: 277° C.

EXAMPLE 116-Ethoxycarbonyl-5-(4-fluorophenyl)-7-isopropyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR42##

11.35 g (50 mmol) of 2,3-dichloro-4,5-dicyanobenzoquinone are added to asuspension of 19.4 g (50 mmol) of the compound from Example 10 in 1 l ofdichloromethane and the mixture is stirred at room temperature for 2 h.It is then washed three times with water, and the organic phase istreated with sodium sulphate and active carbon, filtered andconcentrated to dryness. 17.5 g (91% of theory) of colorless solidremain.

m.p.: 214° C.

EXAMPLE 12 AND EXAMPLE 135-(4-Fluorophenyl)-6-hydroxymethyl-7-isopropyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR43##5-(4-Fluorophenyl)-6-hydroxymethyl-7-isopropyl-1-methyl-4-oxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR44##

A product mixture of the abovementioned compounds 12 and 13, which isseparated in a column (φ 6 cm) on 400 g of 230-400 mesh silica gel usinga gradient of petroleum ether/ethyl acetate (2:1) to (1:3), is obtainedfrom 13.5 g (35 mmol) of the compound from Example 11 and 85.5 ml (128mmol) of a 1.5 M solution of diisobutyl aluminum hydride in tolueneanalagously to the process of Example 4.

    ______________________________________                                        R.sub.f : (petroleum ether/ethyl acetate, 1:1)                                          Ex. 12 = 0.5                                                                  Ex. 13 = 0.2                                                        Yield:    Ex. 12 = 2.4 g (20% of theory) of colorless                                   solid                                                                         Ex. 13 = 1.9 g (17% of theory) of colorless                                   solid                                                               m.p.:     Ex. 12 = 208° C.                                                       Ex. 13 = 197° C.                                             ______________________________________                                    

EXAMPLE 145-(4-Fluorophenyl)-6-formyl-7-isopropyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR45##

1.4 g (68% of theory) of the title compound are obtained as colorlesscrystals from 2.1 g (6 mmol) of the compound from Example 12 in 320 mlof dichloromethane using 2.4 g of alumina and 5.2 g (24 mmol) ofpyridinium chlorochromate analogously to the process of Example 5.

m.p.: 217° C.

EXAMPLE 15(E)-3-[5-(4-Fluorophenyl)-7-isopropyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl)prop-2-enal##STR46##

Analogously to the procedure for Example 6, 0.25 g (8.4 mmol) of 80%strength sodium hydride, 1.2 g (4.2 mol) of diethyl2-(cyclohexylamino)-vinyl-phosphonate and 1.2 g (3.5 mmol) of thecompound from Example 14 are reacted in a total of 36 ml of anhydroustetrahydrofuran, the mixture being heated under reflux for 1 h.

Yield: 1.2 g (93% theory) of yellowish crystals.

m.p.: 202° C.

EXAMPLE 16 Methylerythro-(E)-7-[5-(4-fluorophenyl)-7-isopropyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoate##STR47##

Analogously to the procedures for Example 7 and 8, 140 mg (10% oftheory) of the title compound are obtained as colorless crystals from1.1 g (3 mmol) of the compound from Example 15.

m.p.: 168° C. (from ether/petroleum ether).

EXAMPLE 175-(4-Fluorophenyl)-6-formyl-7-isopropyl-1-methyl-4-oxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR48##

Analogously to the procedure for Example 5, a mixture, which isseparated by column chromatography on silica gel usingdichloromethane/methanol 40:1, is obtained from 1.72 g (5 mmol) of thecompound from Example 13.

Yield: 0.83 g (51% of theory) of colorless crystals.

m.p.: 211° C. from dichloromethane/ether.

R_(f) =0.33 (chloroform/methanol 20:1).

As a by-product, 0.55 g (34% of theory) of5-(4-fluorophenyl)-6-formyl-7-isopropyl-1-methyl-4-oxo-1,4-dihydro-pyrido(2,3-d)pyrimidineare obtained as a colorless foam.

R_(f) =0.24 (chloroform/methanol 20:1).

¹ H-NMR (CDCl₃): δ=6.95-7.1 (m, 4H); 6.2 (d, 1H); 5.18 (dd, 1H); 4.25(m, 1H); 4.07 (m, 1H); 3.75 (s, 3H); 3.6 (b, 1H); 3.29 (m, 1H); 3.12 (s,3H); 2.4 (b, 1H); 2.4 (m, 2H); 1.15-1.45 (m, 2H); 1.15 (m, 6H).

EXAMPLE 18 Methylerythro-(E)-7-[5-(4-fluorophenyl)-7-isopropyl-1-methyl-4-oxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoate##STR49##

Analogously to the procedures for Example 15, 7 and 8, 115 mg (10% oftheory) of colorless crystals are obtained from 0.82 g (2.5 mmol) of thecompound from Example 17.

m.p.: 139° C. (dichloromethane/ether).

EXAMPLE 19E/Z-1-(4-Fluorophenyl)-2-methoxycarbonyl-4-methyl-pent-1-en-3-one##STR50##

Analogously to the procedure for Example 1, 840.7 g (84% of theory) ofthe title compound are obtained as a yellowish oil from 496.5 g (4 mol)of 4-fluorobenzaldehyde and 576.7 g (4 mol) of methyl isobutyrylacetatein 1 l of isopropanol using 22.5 ml of piperidine and 13.5 ml of glacialacetic acid.

b.p.: 150°-152° C. (4 mbar).

EXAMPLE 20(E)-3-[1-Ethyl-5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]prop-2-enal##STR51##

Starting from the compound from Example 19 and 6-amino-1-ethyl-uracil,the compound is obtained as yelllowish crystals analogously to theprocedures for Example 10, 11, 4, 14 and 15.

m.p.: 208° C.

EXAMPLE 21 Methylerythro-(E)-7-[1-ethyl-5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoate##STR52##

Analogously to the procedures for Example 7 and 8, 0.5 g (33% of theory)of the title compound is obtained as a colorless solid from 1.15 g (3mmol) of the compound from Example 20.

m.p.: 155° C.

EXAMPLE 22E-3-[1-Ethyl-5-(4-fluorophenyl)-7-isopropyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-prop-2-enal##STR53##

A solution of 1.9 g (5 mmol) of the compound from Example 20 in 15 ml oftetrahydrofuran is added dropwise under argon and with ice cooling to asuspension of 0.18 g (6 mmol) of 80% strength sodium hydride in 10 ml ofanhydrous tetrahydofuran. After 20 min, 1.1 ml (18 mmol) of methyliodide are added and the mixture is stirred overnight at 50° C. 50 ml ofwater are added cautiously, the mixture is extracted twice with ethylacetate, and the combined organic phases are washed with sodium chloridesolution, dried over sodium sulphate and concentrated to dryness. Columnchromatography (φ 3 cm) on 50 g of silica gel (230-400 mesh) usingpetroleum ether/ethyl acetate (5:1) gives 1.0 g (51% of theory) ofyellowish amorphous solid.

UV (MeOH): λ max.=304 nm.

EXAMPLE 23 Methylerythro-(E)-7-[1-ethyl-5-(4-fluorophenyl)-7-isopropyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido-(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoate##STR54##

Analogously to the procedures for Example 7 and 8, 0.38 g (30% oftheory) of the title compound is obtained as colorless crystals from 1.0g (2.5 mmol) of the compound from Example 22.

m.p.: 123° C. from ether.

EXAMPLE 245-(4-Fluorophenyl)-7-isopropyl-6-methoxycarbonyl-2,4-dioxo-1,2,3,4,5,8-hexahydro-pyrido(2,3-d)pyrimidine##STR55##

12.7 g (0.1 mol) of 6-amino-pyrimidine-2,4(1H, 3H)-dione and 50 g (0.2mol) of the compound from Example 19 are stirred overnight at 140° C. in500 ml of dimethylformamide. The mixture is filtered off hot from alittle precipitate, poured onto 1 l of ice water and extracted threetimes with ethyl acetate. The organic phases are concentrated in vacuoand the residue is stirred thoroughly in methanol.

Yield: 22.8 g (64% of theory) of yellowish crystals.

m.p.: 274° C.

EXAMPLE 255-(4-fluorophenyl)-6-hydroxymethyl-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR56##

The title compound is prepared analogously to the procedure for Example11 and Example 4, a total of 6.5 mol equivalents of diisobutylaluminumhydride being used in this case.

Yield: 1.4 g (20% of theory) of colorless crystals.

m.p.: 194° C. (semi-methoxide).

EXAMPLE 265-(4-Fluorophenyl)-6-formyl-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR57##

4.94 g (14.3 mmol) of the compound from Example 25, 3.1 g of neutralalumina and 6.45 g (30 mmol) of pyridinium chlorochromate are reactedanalogously to Example 5.

Yield: 3.25 g (69% of theory) of yellowish solid.

m.p.: 232° C. (from ether).

EXAMPLE 27(E)-3-[5-(4-Fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]prop-2-enal##STR58##

The title compound is prepared from 0.9 g (30 mmol) of 80% strengthsodium hydride, 2.8 g (10.8 mmol) of diethyl2-(cyclohexylamino)-vinyl-phosphonate and 2.95 g (9 mmol) of thecompound from Example 26 analogously to the process of Example 6.

Yield: 1.0 g (31% of theory) of yellowish crystals.

m.p.: 255° C.

EXAMPLE 28 Methyl(E)-7-[5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-5-hydroxy-3-oxo-hept-6-enoate##STR59##

0.28 g (9.3 mmol) of 80% strength sodium hydride, 0.97 g (8.4 mmol) ofmethyl acetoacetate, 8.6 ml (14 mmol) of 15% strength butyllithium and0.99 g (2.88 mmol) of the compound from Example 27 are reactedanalogously to the procedure for Example 7.

Yield: 1.4 g of crude product.

EXAMPLE 29 Methylerythro-(E)-7-[5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoate ##STR60##

The title compound is obtained analogously to the procedure for Example8 from 1.4 g (2.8 mmol) of the product from Example 28.

Yield: 190 mg (14% of theory) of colorless solid.

m.p.: 148° C.

The examples shown in Table 1 were prepared analogously to the procedurefor Example 9 from the compounds of Examples 16, 18, 21, 23, 29, 44, 50and 53.

    __________________________________________________________________________     ##STR61##                                                                    Ex.                                                                              B  D  E         Y    m.p. (°C.)                                                                     FAB-MS                                        __________________________________________________________________________    30                                                                                ##STR62##                                                                       H  CH.sub.3                                                                                 ##STR63##                                                                         179 (Decomp.)                                                                         494 (M + H); 508 (M + Na)                     31                                                                                ##STR64##                                                                       H  CH.sub.3                                                                                 ##STR65##                                                                         183 (Decomp.)                                                                         480 (M + H); 502 (M + Na)                     32                                                                                ##STR66##                                                                       H  CH.sub.2 CH.sub.3                                                                        ##STR67##                                                                         122 (Decomp.)                                                                         508 (M + H); 530 (M + Na)                     33                                                                                ##STR68##                                                                       CH.sub.3                                                                         CH.sub. 2 CH.sub.3                                                                       ##STR69##                                                                         117 (Decomp.)                                                                         522 (M + H); 544 (M + Na)                     34                                                                                ##STR70##                                                                       H  H                                                                                        ##STR71##                                                                         203 (Decomp.)                                                                         480 (M + H); 502 (M + Na)                     35                                                                                ##STR72##                                                                       H  CH.sub.2 CH.sub.3                                                                        ##STR73##                                                                         184° (Decomp.)                                                                 506 (M + H); 528 (M + Na)                     36                                                                                ##STR74##                                                                       CH.sub.3                                                                         CH.sub.2 CH.sub.3                                                                        ##STR75##                                                                         148° (Decomp.)                                                                 520 (M + H); 542 (M + Na)                     37                                                                                ##STR76##                                                                       H                                                                                 ##STR77##                                                                               ##STR78##                                                                         amphorous                                                                             570 (M + H); 592 (M + Na)                     __________________________________________________________________________

EXAMPLE 38trans-6-{2-[1-Ethyl-5-(4-fluorophenyl)-7-isopropyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one##STR79##

208 mg (0.4 mmol) of the compound from Example 33 are dissolved in 10 mlof water, 0.4 ml (0.4 mmol) of 1 N hydrochloric acid is added and it isextracted five times with dichloromethane. The combined organic phasesare dried over magnesium sulphate and concentrated in vacuo, and theresidue is boiled in 15 ml of toluene in a water separator for 18 h.After concentrating, the residue is chromatographed on 20 g of silicagel (230-400 mesh) in a column (diameter 2 cm) using petroleumether/ethyl acetate (1:1).

Yield: 140 mg (73% of theory) of amorphous colorless solid.

¹ H-NMR (CDCl₃): δ=1.25-1.7 (m, 11H, CH(CH₃)₂, CH₂ -CH₃, O--CH--CH₂--C(OH)); 2.03 (d, 1H, OH); 2.5-2.7 (m, 2H, CH₂ --C═O); 3.8 (s, 1H,N--CH₃); 3.9 (m, 1H, CH--(CH₃)₂); 4.2 (m, 1H, CH--O); 4.5 (q, 2H,N--CH₂); 5.1 (m, 1H, CH--O); 5.35 (dd, 1H, olefin-H); 6.3 (d, 1H,olefin-H); 6.95-7.15 (m, 4H, aromatic-H).

EXAMPLE 39 E,Z-1-Cyclopropyl-3-(4-fluorophenyl)-2-methoxycarbonyl-prop-2-en-1-one##STR80##

Analogously to Example 1, 43.2 g (87%) of the title compound of b.p.(140°-48° C./0.2 mbar) are obtained from 282.4 g (2 mol) of methyl3-cyclopropyl-3-oxopropionate [W. F. Berkowitz, A. A. Ozorio, J. Org.Chem. 36, 3787-92 (1971)] and 260.4 g (2.1 mol) of 4-fluorobenzaldehyde.

EXAMPLE 40(E)-3-[7-Cyclopropyl-1-ethyl-5-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-prop-2-enal##STR81##

Starting from 6-amino-1-ethyl-uracil and the compound from Example 36,the title compound is prepared analogously to the procedures of Examples24, 11, 4, 5 and 15.

Melting point: 236° C.

EXAMPLE 41 Methylerythro-(E)-7-[7-cyclopropyl-1-ethyl-5-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoate##STR82##

The title compound is obtained from the compound of Example 40 inanalogy to the procedures of Examples 7 and 8.

Yield: 32% of theory, melting point 123° C. (dichloromethane), petroleumether).

The compounds shown in Table 2 were prepared in analogy to theprocedures of Examples 24, 11, 4 and 5 starting from the compounds ofExamples 1 to 19:

                  TABLE 2                                                         ______________________________________                                         ##STR83##                                                                    Example No.                                                                            Y            E          m.p. (°C.)                            ______________________________________                                        42                                                                                      ##STR84##                                                                                  ##STR85## 253° C.                               43                                                                                      ##STR86##   (CH.sub.2).sub.2 CH.sub.3                                                                156° C.                               44                                                                                      ##STR87##   CH.sub.2 CH.sub.3                                                                        217° C.                               ______________________________________                                    

EXAMPLE 45E-3-[7-Cyclopropyl-1-ethyl-5(4)-fluorophenyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]prop-2-enal##STR88##

The compound is prepared from the compound of Example 40 analogously tothe procedure for Example 22.

Yield: 56% of theory, melting point 147° C.

EXAMPLE 461-Allyl-5-(4-flouorophenyl)-6-formyl-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidine##STR89##

0.2 g (6.5 mmol) of 80% strength sodium hydride are added with icecooling to a suspension of 2.13 g (6.5 mmol) of the compound fromExample 26 in 20 ml of dimethylformamide. The mixture is stirred at roomtemperature for 10 min until everything has dissolved.

0.79 g (6.5 mmol) of allyl bromide are then added dropwise and themixture is stirred at room temperature for 1 h. It is then poured onto50 ml of ice water and the mixture is extracted twice with 50 ml ofethyl acetate. The organic phases are washed with saturated sodiumchloride solution, then dried over sodium sulphate and concentrated. Theresidue is chromatographed on 60 g of silica gel (230-400 mesh), columndiameter 4 cm using petroleum ether/ethyl acetate (2:1).

Yield: 0.95 g (40%) of colorless crystals of melting point 154° C. (fromether, petroleum ether).

EXAMPLE 475-(4-Fluorophenyl)-6-formyl-1,7-diisopropyl-2,4-dioxo-1,2,3,4-tetrahydro(2,3-d)pyrimidine##STR90##

The compound is obtained from the compound of Example 26 and isopropyliodide analogously to the process for Example 43, the mixture being keptat 50° C. for 18 h.

Yield: 36% of theory, melting point 197° c.

EXAMPLE 481-Benzyl-5-(4-fluorophenyl)-6-formyl-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro(2,3-d)pyrimidine##STR91##

Analogously to the procedure of Example 46 from the compound of Example26 and benzyl bromide.

Yield: 37% of theory, melting point 237° C.

EXAMPLE 491,3-Dibenzyl-5-(4-fluorophenyl)-6-formyl-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro(2,3-d)pyrimidine##STR92##

The compound is obtained in the preparation of Example 48 as a secondproduct. It is isolated by silica gel chromatography using petroleumether/ethyl acetate.

Yield: 24% of theory, amorphous colorless solid.

¹ H-NMR (CDCl₃): δ=1.3 (d, 6H), 3.95 (hept. 1H), 5.13 (s, 2H), 5.67 (s,2H), 7.15-7.5 (m, 14H), 9.6 (s, 1H).

The compounds shown in Table 3 were prepared in analogy to theprocedures of Examples 7, 8 and 15.

                                      TABLE 3                                     __________________________________________________________________________     ##STR93##                                                                    Ex. No.                                                                             B   D       E           Y     m.p. (°C.)                         __________________________________________________________________________    50                                                                                   ##STR94##                                                                        CH.sub.3                                                                              C.sub.2 H.sub.5                                                                            ##STR95##                                                                          amphorous                                 51                                                                                   ##STR96##                                                                        H       CH.sub.2CHCH.sub.2                                                                         ##STR97##                                                                          167                                       52                                                                                   ##STR98##                                                                        H                                                                                      ##STR99##                                                                                 ##STR100##                                                                         137                                       53                                                                                   ##STR101##                                                                       H       CH.sub.2C.sub.6 H.sub.5                                                                    ##STR102##                                                                         177                                       54                                                                                   ##STR103##                                                                       CH.sub. 2C.sub.6 H.sub.5                                                              CH.sub.2C.sub.6 H.sub.5                                                                    ##STR104##                                                                          82                                       55                                                                                   ##STR105##                                                                       H       C.sub.6 H.sub.5                                                                            ##STR106##                                                                         194                                       56                                                                                   ##STR107##                                                                       H       CH.sub.2CH.sub.2CH.sub.3                                                                   ##STR108##                                                                         153                                       57                                                                                   ##STR109##                                                                       H       C.sub.2 H.sub.5                                                                            ##STR110##                                                                         amphorous*                                __________________________________________________________________________     *In the preparation of Example 57, the reaction is not carried out using      hydrogen peroxide, but the crude product is stirred for 3 h at room           temperature in a 200fold amount of methanol                              

EXAMPLE 58 Ethyl 4-fluorobenzoyl acetate ##STR111##

21.7 g (0.72 mol) of sodium hydride (80% strength, 20% mineral oil) areweighed into one liter of diethyl ether p.a. and 85.5 g (127 ml, 0.72mol) of diethyl carbonate are then added. A solution of 100 g (0.72 mol)of 4-fluoroacetophenone in 300 ml of diethyl ether is added dropwise tothis solution at boiling heat over a period of 4 hours (an efficientmechanical stirrer is necessary; a viscous suspension is formed). Themixture is then heated under reflux for a further hour, then cooled toabout 5° C. and a solution of 50 ml of acetic acid and 100 ml of Et₂ Ois first added dropwise at this temperature under N₂. About 500 ml of H₂O is then added dropwise and the organic phase is separated off. Theaqueous phase is extracted again with Et₂ O (2×400 ml), and the combinedethereal phases are washed with NaHCO₃ solution, dried over MgSO₄ andconcentrated. The residue is distilled through a short Vigreux column.

Yield: 93 g (60%) b.p. 0.4 mm 99°-102° C.

EXAMPLE 59 Ethyl 2-(4-fluorobenzoyl)-4-methyl-pent-2-ene-carboxylate##STR112##

A solution of 210 g (1 mol) of ethyl 4-fluorobenzoyl acetate and 144 g(2 mol) of 2-methylpropanol are stirred overnight at 50° C. in 100 ml ofisopropanol containing 7 ml of pyridine and 5 ml of acetic acid. Afterreduction is complete, the mixture is concentrated at about 15 Torr andthe crude product (270 g˜85% of theory) is further reacted withoutfurther purification.

EXAMPLE 601-Ethyl-7-(4-fluorophenyl)-6-formyl-5-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro(2,3-d)pyrimidine##STR113##

The title compound is prepared analogously to the reactions of Example24, 3, 4 and 5 starting from the compound of Example 59 with6-amino-1-ethyl-uracil.

Melting point: 216° C.

EXAMPLE 61 Methylerythro-(E)-7[1-ethyl-7-(4-fluorophenyl-5-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoate##STR114##

The title compound is obtained from the compound of Example 60analogously to the procedures of Examples 7 and 8.

Yield: 30% of theory, melting point: 157° C.

EXAMPLE 62

The serum cholesterol-lowering action of the compounds according to theinvention on the blood cholesterol values of dogs was discovered infeeding experiments of several weeks duration. For this purpose, thesubstance to be investigated was given together with the feed p.o. oncedaily in a capsule to healthy Beagle dogs over a period of severalweeks. Cholestyramine (4 g/100 g of feed) as the gallic acid sequestrantwas additionally mixed with the feed during the entire experimentalperiod, i.e. before, during and after the administration period of thesubstance to be investigated.

Venous blood was taken from the dogs twice weekly and the serumcholesterol was determined enzymatically using a commercial test kit.The serum cholesterol values during the administration period werecompared with the serum cholesterol values before the administrationperiod (controls).

It is understood that the specification and examples are illustrativebut not limitative of the present invention and that other embodimentswithin the spirit and scope of the invention will suggest themselves tothose skilled in the art.

What is claimed is:
 1. A substituted pyrido[2,3-d]pyrimidine of theformula (Ia) or (b) ##STR115## in which A represents phenyl which isoptionally monosubstituted to tetrasubstituted by identical or differentstraight-chain or branched substituents from the group consisting ofalkyl, alkoxy and alkoxycarbonyl each having up to 8 carbon atoms, whichmay in turn be substituted by trifluoromethyl, hydroxyl, alkoxy havingup to 4 carbon atoms, phenyl or phenoxy, or is substituted by phenyl,phenoxy, phenylthio, phenylsulphonyl, fluorine, chlorine, bromine,nitro, cyano, trifluoromethyl or phenyl which benzyloxy orrepresentsstraight-chain or branched alkyl, each having up to 8 carbon atoms, Brepresents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,orrepresents trifluoromethyl or straight-chain or branched alkyl havingup to 10 carbon atoms, which is optionally substituted by fluorine,chloride, bromine, hydroxyl, cyano, azido, trifluoromethyl, methylthio,methylsulphonyl, alkoxy having up to 6 carbon atoms or by phenyl,phenyloxy or phenylthio, where the phenyl radicals may bemonosubstituted or disubstituted by identical or different substituentsfrom the group consisting of fluorine, chlorine, bromine, cyano,trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl,alkoxy, alkylthio and alkylsulphonyl each having up to 6 carbon atoms,or represents phenyl, which is optionally substituted by fluorine orchlorine D represents hydrogen orrepresents cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, or represents straight-chain or branchedalkyl having up to 10 carbon atoms, which is optionally substituted byfluorine, chlorine, bromine, hydroxyl or alkoxy having up to 6 carbonatoms, E has the meaning mentioned above for A and is identical ordifferent, orrepresents hydrogen or represents cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, or represents straight-chain or branchedalkyl having up to 10 carbon atoms, which is optionally substituted byfluorine, chlorine, bromine, straight-chain or branched alkyl having upto 6 carbon atoms, or phenyl, Y and Z are identical or different andrepresent a group of the formula ##STR116## or Y represents athiocarbonyl group, X represents a group of the formula --CH₂ --CH₂ --or --CH═CH-- and R represents a group of the formula ##STR117## in whichR⁸ denotes hydrogen or straight-chain or branched alkyl having up to 8carbon atoms, andR⁹ denotes hydrogen or straight-chain or branched alkylhaving up to 8 carbon atoms or benzyl, or denotes phenyl or a cation,orpharmaceutically acceptable salts thereof.
 2. A substitutedpyrido[2,3-d]pyrimidines of the formula ##STR118## wherein A representsphenyl, optionally, mono- or disubstituted by C₁ -C₄ -alkyl, phenoxy,fluorine or trifluoro-methyl, or represents straight or branched C₁ -C₄-alkyl,B represents phenyl, optionally mono- or disubstituted byfluorine, orC₁ -C₄ -alkyl, or cyclopropyl, D represents hydrogen, orrepresents straight or branched C₁ -C₄ -alkyl, E represents hydrogen,straight or branched C₁ -C₄ -alkyl orphenyl, or benzyl, Y represents thegroup ##STR119## Z represents the group ##STR120## X represents--CH═CH--, R represents a group of the formula ##STR121## R⁹ representshydrogen, a straight or branched C₁ -C₄ -alkyl, or denotes a sodium orpotassium ion,or pharmaceutically accetable salts thereof.
 3. A compoundaccording to claim 1, wherein such compound is methylerythro-(E)-7-[5-(4-fluorophenyl)-7-isopropyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoateof the formula ##STR122## or a pharmaceutically acceptable salt thereof.4. A compound according to claim 1, wherein such compound is methylerythro-(E)-7-[1-ethyl-5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoateof the formula ##STR123## or a pharmaceutically acceptable salt thereof.5. A compound according to claim 1, wherein such compound is methylerythro-(E)-7-[5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoateof the formula ##STR124## or a pharmaceutically acceptable salt thereof.6. A compound according to claim 1, wherein such compound is7-[5-fluorophenyl)-7-isopropyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)-pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoicacid of the formula ##STR125## or a pharmaceutically acceptable saltthereof.
 7. A compound according to claim 1 wherein such compound is7-[5-(4-fluorophenyl)-7-isopropyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)-pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoicacid of the formula ##STR126## or a pharmaceutically acceptable saltthereof.
 8. A compound according to claim 1, wherein such compound is7-[5-(4-fluorophenyl)-7-isopropyl-1-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)-pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoicacid of the formula ##STR127## or a pharmaceutically acceptable saltthereof.
 9. A compound according to claim 1, wherein such compound ismethylerythro-(E)-7-[7-cyclopropyl-1-ethyl-5-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoateof the formula ##STR128## or a pharmaceutically acceptable salt thereof.10. An HMG-CoA reductase inhibiting composition comprising an amounteffective thereof of a compound of a pharmaceutically acceptable saltthereof according to claim 1 and a diluent.
 11. A method of inhibitingHMG-CoA reductase in a patient in need thereof which comprisesadministering to such patient an amount effective therefor of a compoundor pharmaceutically acceptable salt thereof according to claim
 1. 12.The method according to claim 11, wherein such compound ismethylerythro-(E)-7-[5-(4fluorophenyl)-7-isopropyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoate,methylerythro-(E)-7-[1-ethyl-5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6yl]-3,5-dihydroxy-hept-6-enoate,methylerythro-(E)-7-[5-(4-fluorophenyl)-7-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6yl]-3,5-dihydroxy-hept-6-enoate,7-[5-(4-fluorophenyl)-7-isopropyl-1-methyl-2,4-dioxo-1,2,3,4-terahydro-pyrido(2,3-d)-pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoicacid,7-[5-(4-fluorophenyl)-7-isopropyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)-pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoicacid,7-[5-(4-fluorophenyl)-7-isopropyl-1-benzyl-s,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)-pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoicacid, or methylerythro-(E)-7-[7-cyclopropyl-1-ethyl-5-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrido(2,3-d)pyrimidin-6-yl]-3,5-dihydroxy-hept-6-enoate,ora pharmaceutically acceptable salt thereof.